Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

ZnO nanoparticle interactions with phospholipid monolayers

Aqueous ZnO nanoparticle dispersions interaction with a dioleoyl phosphatidylcholine (DOPC) monolayer is reported in this paper. ZnO-DOPC interactions were investigated using rapid cyclic voltammetry (RCV) by focusing on the effect of the interactions on the characteristics of the capacitance current peaks representing two potential induced phase transitions. Results showed: - (1) The order of interaction of common commercially sourced nanoparticles with DOPC coated Hg electrodes was NanoTek>NanoShield>metals basis. This extent of interaction was inversely related to the ZnO particle size where the metals basis nanoparticles were strongly aggregated. The contribution of the non-ionic dispersant added by manufacturer to the NanoTek and NanoShield interaction was uncertain. (2) Freshly prepared aqueous Nanosun ZnO nanoparticle (~25 nm) dispersions interacted with and penetrated DOPC coated Hg electrodes. Aggregation of the nanoparticles, coating of the ZnO with phosphate and coating of the ZnO with fulvic acid minimised ZnO-DOPC interaction. (3) In-house synthesised ZnO nanoparticles of lower primary particle size (~6 nm) than Nanosun ZnO nanoparticles interacted strongly with DOPC coated Hg electrodes with no evidence of penetration of the nanoparticle in the DOPC monolayer. Even after considerable aggregation of the particle to between 1 and 10 μm, a strong interaction of the in-house synthesised ZnO with DOPC was observed

Understanding stress-induced disorder and breakage in organic crystals: beyond crystal structure anisotropy.

Crystal engineering has advanced the strategies for design and synthesis of organic solids with the main focus being on customising the properties of the materials. Research in this area has a significant impact on large-scale manufacturing, as industrial processes may lead to the deterioration of such properties due to stress-induced transformations and breakage. In this work, we investigate the mechanical properties of structurally related labile multicomponent solids of carbamazepine (CBZ), namely the dihydrate (CBZ·2H2O), a cocrystal of CBZ with 1,4-benzoquinone (2CBZ·BZQ) and the solvates with formamide and 1,4-dioxane (CBZ·FORM and 2CBZ·DIOX, respectively). The effect of factors that are external (e.g. impact stressing) and/or internal (e.g. phase transformations and thermal motion) to the crystals are evaluated. In comparison to the other CBZ multicomponent crystal forms, CBZ·2H2O crystals tolerate less stress and are more susceptible to breakage. It is shown that this poor resistance to fracture may be a consequence of the packing of CBZ molecules and the orientation of the principal molecular axes in the structure relative to the cleavage plane. It is concluded, however, that the CBZ lattice alone is not accountable for the formation of cracks in the crystals of CBZ·2H2O. The strength and the temperature-dependence of electrostatic interactions, such as hydrogen bonds between CBZ and coformer, appear to influence the levels of stress to which the crystals are subjected that lead to fracture. Our findings show that the appropriate selection of coformer in multicomponent crystal forms, targetting superior mechanical properties, needs to account for the intrinsic stress generated by molecular vibrations and not solely by crystal anisotropy. Structural defects within the crystal lattice, although highly influenced by the crystallisation conditions and which are especially difficult to control in organic solids, may also affect breakage

Significance of particle size and charge capacity in TiO2 nanoparticle-lipid interactions

The activity of submicron sized titanium oxide (TiO2) particles towards biomembrane models is coupled to their charge carrying capacity and their primary particle size. Experiments: Electrochemical methods using a phospholipid layer on mercury (Hg) membrane model have been used to determine the phospholipid monolayer activity of TiO2 as an indicator of biomembrane activity. The particles were characterised for size, by dynamic light scattering (DLS) and scanning electron microscopy (SEM), and for charge, by acid-base titration. Findings: TiO2 nanoparticles aggregate in 0.1 mol dm-3 solutions of KCl. The charge capacity of TiO2 nanoparticles depends on their primary particle size and is unaffected by aggregation. TiO2 particles of ~40 nm primary particle size interact significantly with phospholipid layers. Aggregation of these particles initially has a small effect on this interaction but long term aggregation influences the interaction whereby the aggregates penetrate the lipid layer rather than adsorbing on the surface. Fulvic acid does not inhibit the ~40 nm particle/phospholipid interaction. P25 TiO2 particles of larger particle size interact less strongly with phospholipid layers and the interaction is alleviated following particle aggregation. The semiconductor properties of TiO2 are evident in voltammograms showing electron transfer to TiO2 adsorbed on uncoated Hg

Controlling polymorphism: general discussion

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